Mechanochemical synthesis of organoselenium compounds

We disclose herein a strategy for the rapid synthesis of versatile organoselenium compounds under mild conditions. In this work, magnesium-based selenium nucleophiles are formed in situ from easily available organic halides, magnesium metal, and elemental selenium via mechanical stimulation. This process occurs under liquid-assisted grinding (LAG) conditions, requires no complicated pre-activation procedures, and operates broadly across a diverse range of aryl, heteroaryl, and alkyl substrates. In this work, symmetrical diselenides are efficiently obtained after work-up in the air, while one-pot nucleophilic addition reactions with various electrophiles allow the comprehensive synthesis of unsymmetrical monoselenides with high functional group tolerance. Notably, the method is applied to regioselective selenylation reactions of diiodoarenes and polyaromatic aryl halides that are difficult to operate via solution approaches. Besides selenium, elemental sulfur and tellurium are also competent in this process, which showcases the potential of the methodology for the facile synthesis of organochalcogen compounds.

In my reading of the manuscript, the key advance is the discovery that aryl diselenides can be formed via the LAG of elemental selenium and various aryl halides.The halides are typically fairly reactive (pyrimidine chloride, iodides, bromides, etc…) but the overall scope demonstrated is reasonably broad.
The subsequent chemistry seems to be highly precedented.I do not have a long personal history with selenium chemistry, but the examples reported here seem like natural extensions of known diselenide mechanochemistry, for example those presented in ref. 34.Essentially, the advance is that this known mechanochemical reactant can be generated in situ as an intermediate in a single pot.Certainly this is useful, and the observation is not obvious, but I am not convinced in the current paper that the novelty and impact is appropriate for this journal.From a mechanochemical reactivity point of view, the result is empirical, and so it is not clear that there are transferable mechanistic insights that might be applied to other systems.I would of course defer to those with more directly methodological experience that is relevant in the event that I underestimate the significance of the practical implications.
Whether considered further here or elsewhere, the manuscript would benefit from additional editing.The grammar starts well but becomes increasingly erroneous as the paper goes on.A few of these are very easily fixed."Mordified" is used on multiple occasions in place of (I presume) "modified" (and not "mortified")."Mehtod" is another typographical error, as is the missed boldface in 1r.The more problematic involve sentence structure, mismatches between subject and verb, verb tense, etc… Figure 1a does not include examples of Se catalysis or Se based materials, as promised in the text.
I might be missing it, but the top of Figure 4a does not seem to show all reactants required for formation of the products shown.
Reviewer #2: Remarks to the Author: In this paper, Peng, Wei, and their colleagues present a novel approach for synthesizing a range of organoselenium compounds using ball-milling activation of elemental selenium.By utilizing this method, the authors demonstrate the successful synthesis of symmetrical diselenides and unsymmetrical monoselenides, offering valuable insights into the reactivity of selenium under ballmilling conditions.Additionally, the authors showcase gram-scale synthesis in air and the regioselective addition for the synthesis of bioactive organoselenium compounds.Mechanistic studies are also presented to shed light on the underlying reactions.The paper exhibits significant scientific novelty within the field of mechanochemistry and holds promise for practical applications.However, before publication in Nature Communications, several crucial points must be addressed.

Introduction:
The authors should include a discussion on pioneering studies related to the mechanochemical synthesis of Grignard reagents, as this topic is highly relevant to the present research.
Ball-milling process: To provide clarity, the authors should elaborate on whether both magnesium and elemental selenium are activated by the ball-milling process.Furthermore, a more detailed

Responses to the Reviewers' Comments
We thank the reviewer for his/her valuable suggestion and comments.
Dear Editors and Reviewers, We appreciate the efforts you have made to evaluate our work.Thank you for giving us an opportunity to improve our manuscript entitled "Mechanochemical Synthesis of Organoselenium Compounds" (Manuscript Number: NCOMMS-23-22030).We appreciate your valuable comments, which are significantly helpful for us to improve the quality of our manuscript.We have addressed all issues in positive manners, and have revised the manuscript accordingly with new data and their interpretation added.The revised manuscript and marked version with highlighted changes are now resubmitted for your evaluation.Please find our point-by-point responses provided below.

Reviewer: 1
The paper presents the synthesis of various selenides via liquid assisted grinding (LAG).The methods are useful, but in my estimation represent a fairly modest step forward in methodology that likely does not meet the expectations of N. Commun.
In my reading of the manuscript, the key advance is the discovery that aryl diselenides can be formed via the LAG of elemental selenium and various aryl halides.The halides are typically fairly reactive (pyrimidine chloride, iodides, bromides, etc…) but the overall scope demonstrated is reasonably broad.Response: We express our gratitude to the reviewer for recognizing the key advance of our discovery and commented the scope of our method as "reasonably broad".In chalcogenation chemistry, direct conversion of elemental chalcogen into valuable organochalcogenides is impressively appealing as the method obviates the need of sensitive and toxic selenium reagents.Mechanochemistry, an emerging field in organic chemistry, holds the for efficient and user-friendly transformation handling chalcogen elements.
In this study, our primary objective was to establish a highly practical platform for the comprehensive synthesis of organochalcogen compounds.Our scope extends beyond "fairly reactive aryl halides" and encompasses heteroaryl-, electron-withdrawing or electron-donating aryl halides, as well as alkyl halides.This versatile transformation includes conjugate addition, substitution reactions, and transesterification.Remarkably, the reaction can accommodate sensitive protic functional groups, leading to a diverse array of structures with potential applications in bioactivity evaluation.
The subsequent chemistry seems to be highly precedented.I do not have a long personal history with selenium chemistry, but the examples reported here seem like natural extensions of known diselenide mechanochemistry, for example those presented in ref.
34. Essentially, the advance is that this known mechanochemical reactant can be generated in situ as an intermediate in a single pot.Certainly this is useful, and the observation is not obvious, but I am not convinced in the current paper that the novelty and impact is appropriate for this journal.From a mechanochemical reactivity point of view, the result is empirical, and so it is not clear that there are transferable mechanistic insights that might be applied to other systems.I would of course defer to those with more directly methodological experience that is relevant in the event that I underestimate the significance of the practical implications.

Response:
We appreciate the critical analysis of from this reviewer.We were also encouraged to see the reviewer recognized the significance of the practical implications.We also provided additional mechanistic investigation and interpretation in our revised manuscript.This work represents the first instance of a mechanochemical carbonchalcogen bond-forming reaction using elemental chalcogen.It offers one of the most straightforward methods for the systematic synthesis of organochalcogenides.Conventional preformed activated selenium reagents, such as known diselenides, encounter several issues, including relatively high cost, storage challenges (especially concerning the unpleasant smell of alkyl diselenides), and limited commercial availability, among others.As demonstrated in the main text, current methods often rely on the use of expensive transition metals and involve the utilization of large quantities of toxic polar organic solvents.Our current strategy has the potential to address these problems effectively.Throughout the revision process, we conducted extensive investigations into the application scope of the current strategy.This method has demonstrated its capability to efficiently produce a wide range of organochalcogenides with high yields, stepefficiency, and atom-economy.The analysis using NEXAFS spectroscopy, along with preliminary mechanistic investigations, suggests the strategic potential that can combine magnesium-based organochalcogen reagents as coupling partners Whether considered further here or elsewhere, the manuscript would benefit from additional editing.The grammar starts well but becomes increasingly erroneous as the paper goes on.A few of these are very easily fixed."Mordified" is used on multiple occasions in place of (I presume) "modified" (and not "mortified")."Mehtod" is another typographical error, as is the missed boldface in 1r.The more problematic involve sentence structure, mismatches between subject and verb, verb tense, etc… Response: We sincerely apologize for numerous grammatic errors that may have caused inconvenience to the reviewer during the evaluation of our manuscript.We appreciate the meticulous work of this reviewer to point the grammar and spelling errors.We comprehensively checked and modified the text by consulting a native speaker.The corresponding changes could be found in the text with highlighted mark.I might be missing it, but the top of Figure 4a does not seem to show all reactants required for formation of the products shown.Response: Thank you for the comment.We revised Fig. 4a accordingly to include all the required information in our revised manuscript.

Reviewer: 2
In this paper, Peng, Wei, and their colleagues present a novel approach for synthesizing a range of organoselenium compounds using ball-milling activation of elemental selenium.By utilizing this method, the authors demonstrate the successful synthesis of symmetrical diselenides and unsymmetrical monoselenides, offering valuable insights into the reactivity of selenium under ball-milling conditions.Additionally, the authors showcase gram-scale synthesis in air and the regioselective addition for the synthesis of bioactive organoselenium compounds.Mechanistic studies are also presented to shed light on the underlying reactions.The paper exhibits significant scientific novelty within the field of mechanochemistry and holds promise for practical applications.
However, before publication in Nature Communications, several crucial points must be addressed.Response: We thank this reviewer for the very positive evaluation and his/her support for publishing our work in Nature Communication.
Introduction: The authors should include a discussion on pioneering studies related to the mechanochemical synthesis of Grignard reagents, as this topic is highly relevant to the present research.
Ball-milling process: To provide clarity, the authors should elaborate on whether both magnesium and elemental selenium are activated by the ball-milling process.Furthermore, a more detailed explanation of the working hypothesis would greatly benefit the readers.

Response:
We sincerely thank the reviewer for the valuable suggestion, and in response, we have performed Near-edge X-ray absorption fine structure (NEXAFS) spectroscopy experiments to observe the formation of intermediates and we have subsequently incorporated the additional results and analysis into the main text.
In page 5, line 3-10 and line 16-39, we have added "To confirm the generation of magnesium-based selenium nucleophiles under ball-milling conditions, we utilized Near-edge X-ray absorption fine structure (NEXAFS) spectroscopy.NEXAFS measurements were conducted at BL08U1A beamline of Shanghai Synchrotron Radiation Facility (SSRF in China) using magnesium-based selenium nucleophiles 47a, which were prepared through ball milling and then transferred into the soft X-ray optics under an argon atmosphere.The formation of the divalent cationic Mg 2+ species was unequivocally confirmed through the high-energy shift of the Mg K-absorption edge (1317.0eV) in comparison to the Mg 0 edge (1315.0eV) of a standard magnesium flake (Fig. 6a). 89The high resemblance of the NEXAFS spectra at Mg-K, C-K Se-L3 edges between the mechanochemically-prepared 47a and PhSeMgBr prepared in solution 47b 90 (Fig. 5b) supports the formation of similar magnesium-based organoselenium species with carbon-selenium bonds under both ball-milling and solution conditions in THF (Fig. 6a-c).The presence of carbon-selenium bond, arising from the transformation of the C-Br bond in the starting bromobenzene, was supported by the intense 1s-π* transition peaks at approximately 284.0 and 286.2 eV in the C-K NEXAFS spectra (Fig. 6b). 91Additionally, the formation of the monovalent anionic Se 1-species was conclusively confirmed through the low-energy shift of the Se L3-edge absorption peak (1445.3eV) in 47a relative to the Se 0 peak (1446.0eV) in standard selenium power (Fig. 6c). 92The remarkable similarity of Se L3-edge, Mg K-edge and C K-edge NEXAFS spectra of mechanochemically-prepared 47a to those of PhSeMgBr (47b) prepared in solution (Fig. 6a-c) further supports the formation of similar organoselenium species with carbon-selenium bonds under both ball-milling and solution conditions in THF. 60

"
In page 5, we have added "Fig 6 .NEXAFS analysis of a magnesium-based selenium nucleophiles under mechanochemical conditions."In page 1, line 53-76, we described the working hypothesis as the following"In this report, we present a mechanochemical method for synthesizing organoselenium compounds which involves the in situ generation of magnesium-based selenium species through the straightforward process of mixing and grinding organic halides, magnesium, and elemental selenium.Notably, these species exhibit extreme sensitivity to both oxygen and water, leading to their complete conversion into symmetrical diselenides during the work up procedure.Additionally, employing a one-pot process for the addition of electrophiles enabled efficient synthesis of unsymmetrical monoselenides, which proceeded smoothly even in the presence of air.(Fig 1d).We also achieved the successful preparation of magnesium-based organoselenium reagents from polyaromatic aryl halides and diiodoarenes.Notably, it's important to highlight that converting such substrates into organochalcogenides poses challenges when employing conventional solution-based methods.Near edge, X-ray absorption fine structure (NEXAFS) spectroscopy was employed to analyze the generation of the magnesiumbased organoselenium nucleophiles under mechanochemical conditions.The method can be extended to the straightforward synthesis of organoic sulfur and tellurium compounds, suggesting its potential potential to serve as a highly practically foundation for the comprehensive synthesis of organochalcogen compounds."Solvent amount: While the synthetic utility is evident, the use of 12 equivalents of THF, which can be regarded as a solvent amount raises concerns regarding the environmental sustainability and greenness of the strategy.

Response:
To better distinguish the amount of solvent in solution-based condition, we have changed the amount of LAG from "THF (xx eq.)" to "xx µL/mg" in the revised manuscript and Supplementary Information.
In light of our commitment to environmental sustainability and green synthetic strategies, we have reduced the use of Liquid-Assisted Grinding (LAG) THF to 6.0 equivalents.This adjustment has been found to be equivalent in reactivity to using 12.0 equivalents of THF for the synthesis of dichalcogenides.As a result, we have set the amount of THF at 6.0 equivalents and re-evaluated the scope in Figure 2.
Corresponding condition screening details can be found in Supplementary Table 2. Furthermore, using the calculation formula for LAG (η = V [liquid; μL]/m [reagents; mg]), we calculated the "eta" values (microL/mg) of symmetrical dichalcogenides within the range of 1.16-1.62μL/mg.This demonstrates that the amount of THF we utilized aligns with solid-phase ball milling (0-2) μL/mg, as reported in Adv.Synth.Catal.2021, 363, 1246-1271, and does not exceed the solvent amount.Regarding the synthesis of unsymmetrical monochalcogenides, our Supplementary Information (Supplementary Table 3) shows that the reaction can still proceed with 3.0 equivalents of THF.With 6.0 equivalents of THF, the target compound can be obtained with a 76% yield.However, after careful consideration, taking into account factors such as the amount of THF, reaction time, and overall efficiency, we have determined that using 12.0 equivalents of THF achieves efficient synthesis with a 94% yield.Additionally, we calculated the "eta" values (microL/mg) for unsymmetrical chalcogenides in the range of 0.81-1.88μL/mg, which align with the mechanochemical definition of Liquid-Assisted Grinding (LAGs).Spectroscopic evidence: It is essential to obtain spectroscopic evidence confirming the generation of Ar-Se-MgX under ball-milling conditions.Additionally, the existence of a reaction equilibrium between symmetrical diselenides and magnesium-based selenium nucleophiles requires substantiation.The authors should propose a mechanism for this equilibrium.

Response:
We appreciate the insightful suggestion from this reviewer.As the answer of question 2, we provided spectroscopic evidence by using near-edge X-ray absorption fine structure (NEXAFS) spectroscopy, which support the generation of Ar-Se-MgX under ball-milling conditions.The experiments conducted freshly, as shown in Fig 5b, have ruled out the existence of a reaction equilibrium between symmetrical diselenides and magnesium-based selenium nucleophiles.The complete formation of benzeneselenol upon quenching in the glovebox strongly suggests that the formation of symmetrical diselenide was indeed promoted by oxidation in the air during the work up process.As a result, we have made necessary modifications to the text on page 2, line 60-63, page 3, line 1-2 and page 4, line 24-32.
Mechanistic studies: Although the authors provide preliminary mechanistic studies, a conclusive summary or overall reaction pathway is currently absent.The authors should aim to provide a comprehensive understanding of the reaction mechanism.Poorly soluble substrates: While the authors investigated the reaction of the polyaromatic halide 31, it is not considered a poorly soluble compound.To effectively demonstrate the utility of the mechanochemical protocol for reactions with poorly soluble substrates, the authors should investigate a broader range of large polyaromatic halides.Response: Thank you for the kind suggestion.We changed the content limited to large polyaromatic aryl halides without emphasizing poorly soluble compound.Moreover, we further explored the scope as shown in Figure 4b  And In page 1, line 41-45, we have added these references to "Recently, the strategy has been applied to facilitate the oxidative addition of zero valent metals (such as Mg, Mn, Zn, Ca, etc) to organic halides, generating organometallic species for diverse nucleophilic transformations. 48-60".We have also added relevant references 56-59 to the References.

Reviewer: 3
Cheng Peng, Xiaofeng Wei et al. describe a strategy for the synthesis of organoselenium compounds under mild conditions using magnesium-based selenium nucleophiles.These species were formed in situ by milling organic halides, magnesium metal, and elemental selenium under liquid-assisted grinding (LAG) conditions.The method developed, was tested and used to produce symmetrical and asymmetric diselenides.In addition, the methodology was extended to sulfur and tellurium.The manuscripts methodology seems broadly applicable and versatile, therefore it could potentially be of interest to the broad readership of Nature Communications.
However, before the paper could be fully considered for publication there are several questions that need to be addressed.

Figure
Figure 1a does not include examples of Se catalysis or Se based materials, as promised in the text.Response: Thank you for the comment.We have updated the information in Fig 1a accordingly.

Response:
Based on preliminary mechanistic studies, as shown in Fig 5 with additional results and NEXAFS analysis presented in Fig 6, we propose the following reaction process, as shown in Fig 1d.Initially, under ball milling conditions, magnesium undergoes oxidative insertion into aryl halide to form PhMgX (Nature Commun., 12, 6691, (2021)), which subsequently reacts with elemental selenium to produce PhSeMgX (J.Chem.Res., 34, 127-129 (2010)).However, because we open the stainless-steel jar in the air and put 1a in the stainless-steel jar, a portion of PhSeMgX is hydrolyzed to generate PhSeH due to the presence of moisture from the air (Bioorg.Med.Chem.Lett., 29, 126726(2019); Chem.Eur.J., 23, 2405 -2422(2017)) and it is oxidized by the air, forming symmetrical diselenides.Nevertheless, diselenides can be reconverted into selenium nucleophiles in the presence of excessive magnesium (Fig 5c), subsequently converting to unsymmetrical monoselenide in the presence of an electrophile.Accordingly, the main text was modified to address the mechanism issue.As shown in Page 4, Line 17-40 and Page 5, Line 3-10, Line 16-39.